DESCRIPTION (provided by investigator): Invasive brain intervention often results in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the Blood-Brain barrier (BBB) protects the brain tissue from foreign molecules. Laboratory experiments have shown that focused ultrasound (FUS) beams can be used for noninvasive interventions. However, the utilization of FUS in the brain has been seriously limited by the difficulty of delivering FUS through the skull bone. The hypothesis of this grant has been that transcranial therapeutic ultrasound exposures can be delivered noninvasively through an intact skull. During our current grant we continued our initial research and developed methods to allow FUS propagation through the skull at large entrance angles thus making whole brain sonications feasible. We have collaborated with industry to develop a prototype device currently in clinical testing. We have further studied the impact of ultrasound exposures on brain tissue and demonstrated chemotherapy delivery across the BBB and an order of magnitude reduction in the required acoustic power for focal tissue destruction when intravascular microbubbles are used. We have also developed computer simulation programs and new array technology and treatment methods that will improve the delivery of FUS energy. Our study plan is to extend our current research and further explore the feasibility of using intravascular microbubbles to enhance the trans-skull sonications. Successful utilization of the bubbles will eliminate skull heating problems and will enable new therapies. Our goals are: First, to modify our prototype phased array ultrasound system to allow acoustic signal feedback, new treatment planning, and advanced sonication methods to be tested for the localization and control of bubble-enhanced treatments. Second, to perform in vivo dual photon microscopy to increase our understanding of ultrasound induced BBB disruption and tissue destruction at the microscopic resolution. Third, to explore sonication methods for localization of bubble-enhanced therapeutic effects. Fourth, to develop and test treatment planning methods for bubble-enhanced therapy that incorporate image-derived information of the blood vessels networks. Finally, to further test the effectiveness of the ultrasound-induced disruption of the BBB for the delivery of chemotherapeutic agents for the treatment of malignant brain tumors. Our vision is that successful trans-skull delivery of FUS could have a major impact on the treatment of many brain disorders. Therefore this research may have a major impact on patient care. PUBLIC HEALTH RELEVANCE: Invasive brain intervention often result in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the Blood-Brain barrier (BBB) protects the brain tissue from foreign molecules. During our current grant we continued our initial research and developed methods to allow focused ultrasound propagation through the skull such that brain sonications are feasible. We have collaborated with industry to develop a prototype device currently in clinical testing. We plan to further develop the ultrasound methods for brain surgery and targeted chemotherapy delivery. Our vision is that successful trans- skull sonications could have a major impact on the treatment of many brain disorders. Therefore this research may have a major impact on patient care.